MEDIATORS OF ACCELERATED GRAFT ARTERIOSCLEROSIS

移植血管的动脉化是最常见的长期原因， 心脏移植病人的死亡移植物动脉硬化是 弥漫性、环状疾病，特征为 炎性细胞和由平滑肌细胞形成的新生内膜。广泛 多种可溶性介质影响细胞的迁移和增殖， 这些细胞进入移植血管，我们提出两种介质，一氧化氮， 氧化物和转化生长因子-β，是至关重要的发展 移植物动脉硬化 我们的初步数据显示心脏移植后， 人类会产生一氧化氮和其他自由基此外，委员会认为， 我们的数据显示，在移植后的几个月里， 合酶在单核炎性细胞中表达， 大鼠和人类心脏移植物的动脉。一氧化氮可以 对宿主既有利又有害，但硝酸的作用 血管壁中的氧化物未知。我们的首要目标是 确定诱导型一氧化氮合酶的表达模式。 并确定一氧化氮对血管壁的影响。 如果在心脏移植物中合成，转化生长因子β 理论上会损伤内皮细胞， 通过诱导释放血小板衍生的生长物来进行细胞增殖 因子 我们的初步数据表明，这些生长因子的影响可以 通过显性负突变受体的过度表达废除， 体外我们的第二个具体目标是确定转换的作用 生长因子-β和血小板衍生生长因子 移植物动脉硬化，使用一种独特的方法来研究孤立的， 体内修饰的内皮细胞。然后，我们计划在我们的第三个具体目标， 研究转化生长因子β如何影响 内皮细胞中的一氧化氮。 这些目标与本计划中的其他项目直接相关 项目转化生长因子-β诱导内皮细胞 细胞凋亡，这是研究项目1。一氧化氮的调节 在功能失调的内皮细胞中的生产也在项目中进行了探索。 1.在项目2中研究的CMV可以诱导感染的一氧化氮合酶， 细胞项目4中研究的补体固定也可以诱导 一氧化氮的产生。一氧化氮和转化生长 β因子由活化的巨噬细胞释放，巨噬细胞参与 在项目5中研究的细胞介导的免疫过程中的抗原呈递。 因此，许多途径可以导致释放我们所处的介质， 研究，这反过来又导致移植物动脉硬化的发展。

Arteriosclerosis of graft vessels is the most common long-term cause of death of a patient with a transplanted heart. Graft arteriosclerosis is a diffuse, circumferential disease, characterized by an infiltrate of inflammatory cells, and a neointima formed by smooth muscle cells. A wide variety of soluble mediators affect the migration and proliferation of these cells into graft vessels, and we propose that two mediators, nitric oxide and transforming growth factor-beta, are crucial to the development of graft arteriosclerosis. Our preliminary data show that immediately after cardiac transplantation, humans produce a burst of nitric oxide and other radicals. Furthermore, our data show that in the months after transplantation, nitric oxide synthase is expressed in mononuclear inflammatory cells migrating into arteries of cardiac allografts in rats and humans. Nitric oxide can have both beneficial and harmful effects to the host, but the role of nitric oxide in the vessel wall is unknown. Our first specific aim is to determine the pattern of expression of inducible nitric oxide synthase. and determine the effect of nitric oxide on the vessel wall. If synthesized in cardiac allografts, transforming growth factor-beta could in theory damage endothelial cells, and also cause smooth muscle cell proliferation by inducing the release of platelet derived growth factor. Our preliminary data show that the effects of these growth factors can be abrogated by the over-expression of dominant negative mutant receptors in vitro. Our second specific aim is to determine the role of transforming growth factor-beta and platelet derived growth factor in the development of graft arteriosclerosis, using a unique method to study isolated, modified endothelial cells in vivo. We then plan in our third specific aim to examine how transforming growth factor-beta affects the production of nitric oxide in endothelial cells. These aims are directly related to other projects within this program project. Transforming growth factor-beta induces endothelial cell apoptosis, which is studied in Project 1. Regulation of nitric oxide production in dysfunctional endothelial cells is also explored in Project 1. CMV, studied in Project 2, can induce nitric oxide synthase in infected cells. Fixation of complement, studied in Project 4, can also induce production of nitric oxide. Both nitric oxide and transforming growth factor-beta are released by activated macrophages, which are involved in antigen presentation during cell-mediated immunity studied in Project 5. Thus, many pathways could lead to the release of the mediators we are studying, which in turn lead to the development of graft arteriosclerosis.